Therapeutic agents containing thyroid hormones

ABSTRACT

There is disclosed a solid fast dispersing dosage form of a pharmaceutical composition suitable for oral administration comprising: a therapeutic agent which comprises one or more compound thyroid hormone or hormones; from about 80% to about 99.9% of disintegrating agent by mass; from about 0.01% to about 10% of flavoring agent by mass; and from about 0.1% to about 5% mass of lubricating agent by mass; which has utility in the treatment of disorders associated with the improvement of the thyroid hormone function in animals including human beings.

This invention relates to novel pharmaceutical compositions comprisingone or more thyroid hormones, and to their use in the treatment ofdisorders associated with impairment of the thyroid hormone functions inanimals including human beings.

Pharmaceutical compositions comprising solid fast dispersing dosageforms for oral administration have recently become available. The dosageforms are prepared by freeze drying, a relatively slow process, whichinvolves the use of expensive and complicated equipment. Furthermore,fast dispersing dosage forms produced by freeze drying are very friableand extremely moisture sensitive, which makes them difficult to package.For example, when presented in a conventional blister pack they are notsufficiently hard to retain their integrity when a force is applied tobreak the package seal and eject them from the blister. Such tablets arealso unsuitable for conventional packing into bottles. Known freezedried fast dispersing dosage forms have the further disadvantage thatthey are difficult to prepare other than as large tablets.

Therefore it is an object of the invention to provide a solid fastdispersing oral dosage form for a pharmaceutical composition asdescribed herein which avoids all or some of the disadvantages of knownfreeze dried rapidly dispersing dosage forms whilst retaining all orsome of the advantages of fast dispersing dosage forms over moreconventional solid oral dosage forms.

These advantages include good patient compliance as fast dispersingdosage forms are easy to ingest as they disintegrate readily and quicklyin the mouth within seconds imparting a pleasant sensation to the mouth.This can be particularly useful for patients such as children or theelderly who have difficulty in swallowing, as no extra liquid (eg water)is required to take these oral dosage forms. Fast dispersing oral dosageforms have the further advantage that the thyroid hormone activeingredient is presented to the gastro-intestinal tract in a finelydivided particulate form which favours optimal and consistent absorptioninto the body.

To improve convenience and patient compliance the oral dosage forms ofthe present invention may be made of a mass typically ten times smallerthan possible for freeze-dried dosage forms. Small oral dosage formshave the further advantage of minimising the amount of diluents ingestedparticularly when the therapeutic agent is present in very smallamounts, for example the microgram quantities per unit dose required ifthe therapeutic agent is thyroid hormone.

Thyroid hormones as described are useful in the treatment of disordersassociated with improvement of the thyroid hormone function in animalsincluding human beings for example myxedema, cretinism or obesity.Thyroid hormones can be prepared synthetically as the biologicallyactive 1-enantiomer or can be isolated direct from the thyroid gland ofanimals.

Therefore the present invention provides a solid fast dispersing dosageform of a pharmaceutical composition suitable for oral administrationcomprising: a therapeutic agent which comprises at least one thyroidhormone; from about 80% to about 99.9% of disintegrating agent; fromabout 0.01% to about 10% of flavouring agent; and from about 0.1% toabout 5% of lubricating agent, all percentages being percentage mass ofingredient by total mass of the composition (known hereinafter as `bymass`).

Surprisingly, the present invention provides pharmaceutical compositionsgiving the above stated advantages of fast dispersing oral dosage formswithout freeze drying. Freeze drying is a time consuming and expensiveprocess requiring significant capital investment in specialised plantand machinery and high maintenance and operating costs. The productionof the solid fast dispersing oral dosage form of the present inventionby using simple formulation and processing technology results in majorcost savings over production of known rapidly dispersing oral dosageforms. The lubricating agent is added to the composition to aidcompression of the solid dosage form In order to improve palatabilityand patient compliance it has also been found that the composition mustcomprise a flavouring agent. Solid fast dispersing oral dosage forms ofthe invention are less friable than freeze-dried formulations and may bemade into smaller dosage forms than is possible with freeze-driedformulations. Compositions of the present invention have a suitably longshelf life, and disperse in the mouth rapidly in a fine particulate formwith no gritty texture. They are easy and pleasant to administer.

Thyroid hormones comprise the following:

L-3,5,3',5'-tetraiodothyronine (levothyroxine or LT4);

L-3,5,3'-triiodothyronine (liothyronine or LT3);

L-3,3',5'-triiodothyronine (LrT3);

L-3,5-diiodothyronine (LT2); or mixtures thereof. As used herein theterm thyroid hormone should be understood to include allpharmaceutically acceptable salts thereof, preferably sodium salts.

Thyroid hormones may exist as one or more polymorphic forms (for exampleone or more crystalline forms, amorphous forms, phases, solid solutionsand/or mixtures thereof) and the therapeutic agent may include eachpharmaceutically acceptable polymorphic form of thyroid hormones and/ormixtures thereof.

Thyroid hormones may also exist in the form of solvates (for examplehydrates) and the therapeutic agent may include each solvate of thyroidhormones and/or mixtures thereof.

Preferably the therapeutic agent is present in the composition in anamount per unit dose from about 0.1 μg to about 10,000 μg, morepreferably from about 1 μg to about 1000 μg, most preferably, if thetherapeutic agent is LT₄, from about 25 μg to about 300 μg.

It may be beneficial for any of the ingredients of compositions of thepresent invention (including the therapeutic agent) to be in the form ofparticles of very small size, for example as obtained by fluid energymilling. Alternatively the therapeutic agent may be bound (for exampleby sorption, incorporation and/or chemically) to nanoparticles which arecollodial polymeric particles of a size typically less than 1 micron.The distribution of such nanoparticles in the body and hence the sitesof delivery of the therapeutic agent can be effected by coating thesurface of the nanoparticles appropriately (for example with surfactantsor antibodies). The therapeutic agent in the solid dosage form of thepresent invention may, if desired, be associated with other compatible,pharmacologically active ingredients.

Preferably the disintegrating agent comprises a blend of at least twocomponents and each component may independently comprise one or more ofthe following ingredients: pharmaceutical grade starch (eg maizestarch), modified starch (eg pre-gelled starch and/or sodium starchglycollate), agar, bentonite, cellulose, microcrystalline cellulose,methylcellulose, carmellose, croscarmellose sodium, alginic acid, guargum, silicon dioxide and sodium lauryl sulphate; more preferably one ormore of pharmaceutical grade starch and microcrystalline cellulose.Preferably the disintegrating agent is present in an amount from about80% to about 99%, more preferably from about 85% to about 98% by mass ofthe composition.

Preferably the flavouring agent comprises one or more of the following:

a sweetening agent which may be a nutritive or non-nutritive sweetenerpreferably sodium saccharin or aspartame;

a peppermint oil and/or fruit flavour;

a flavour enhancing agent; or

an ingredient or ingredients which may induce the formation of saliva,preferably a pharmaceutically acceptable acid, more preferably anorganic acid, most preferably an acid selected from citric and malicacid.

Preferably the flavouring agent is present in an amount from about 0.1%to about 5%, more preferably from about 1% to about 3%, by mass of thecomposition.

Preferably the lubricating agent is selected from one or more of thefollowing ingredients: magnesium stearate, calcium stearate, stearicacid and mixtures thereof; more preferably magnesium stearate.Preferably the lubricating agent is present in an amount from about 0.1%to about 1% by mass of the composition.

The disintegrating agent may be the sole diluent in the composition, orthe composition may also comprise one or more additional inert diluentor diluents, which may be selected from one or more of the followingingredients: lactose, powdered sugar, sucrose, pharmaceutical gradestarch, kaolin, talc, and pharmaceutically acceptable calcium salts;more preferably selected from sucrose and pharmaceutical grade starch,talc, calcium phosphate and calcium sulphate. The total amount ofdiluent (including the disintegrating agent) may be present in an amountfrom about 90% to about 99.9%, preferably from about 95% to about 99%,more preferably from about 95% to about 98%, by mass of the composition.

The solid oral dosage forms of the invention may further comprise one ormore of the following optional ingredients which are pharmaceuticallyacceptable:

binders, for example starch, gelatin, sugars (such as sucrose, molassesor lactose), and/or natural and synthetic gums (such as acacia, sodiumalginate, extract of Irish moss, carboxymethylcellulose,methylcellulose, ethylcellulose, polyethylene glycol, waxes,microcrystalline cellulose or polyvinylpyrrolidione);

colouring agents, for example conventional pharmaceutically acceptabledyes;

orally acceptable preservatives;

anti-oxidants; and

one or more pharmaceutically acceptable effervescent couple or couples(such as an acid and a carbonate, preferably sodium carbonate and/orsodium bicarbonate) to aid disintegration and improve mouth feel.

The optional ingredients may be present in an amount from a trace amountto about 10% by mass of the composition.

Preferably solid oral dosage forms of the present invention may have ahardness in the range from about 1 to about 6 kp, more preferably fromabout 1 to about 5 kp. It will be appreciated by a person skilled in theart that these ranges should not be considered as limiting, because theactual hardness of a specific solid dosage form of the present inventionwill vary according to the particular formulation and equipment used toprepare the dosage form. The practical limits for the hardness of soliddosage forms of the invention are governed by the minimum hardnessrequired to survive production, packaging, transport and removal fromthe packaging and the maximum hardness which still provides anacceptable mouth feel.

A further aspect of the present invention provides use of a thyroidhormone in the preparation of the pharmaceutical compositions describedherein for the treating of disorders associated with an impairment ofthe thyroid hormone function in animals including human beings.

A still further aspect of the present invention provides a method oftreating disorders associated with an impairment of the thyroid hormonefunction in animals including human beings, which comprisesadministering to a patient in need thereof a therapeutically and/orprophylactically effective amount of a composition according to thepresent invention.

Whilst the precise amount of the therapeutic agent administered in thetreatment described above will depend on a number of factors, forexample the severity of the condition, the age and past medical historyof the patient, and always lies within the sound discretion of theadministering medical practitioner or veterinary a suitable daily doseof a thyroid hormone or administration to animals, including humanbeings, may generally be from about 0.1 μg to about 10,000 μg,preferably from about 1 μg to about 1000 μg, more preferably if thethyroid hormone is LT₄ from about 25 μg to about 300 μg given in asingle dose or in divided doses at one or more times during the day.Compositions of the present invention may be prepared in unit dosageform, therefore each solid oral dosage form may comprise from about 0.1μg to about 10,000 μg, preferably from about 1 μg to about 1000 μg, morepreferably, if the therapeutic agent is LT₄, from about 25 μg to about300 μg (for example 25 μg, 50 μg, 75 μg or 100 μg) of a thyroid hormone.

Pharmaceutical compositions of the present invention may be used inadjunctive therapy with one or more other compounds having activity inthe treatment of disorders associated with an impairment of the thyroidhormone function in animals including human beings. It will beappreciated that the term treatment as used herein includes prophylacticuse of the pharmaceutical composition of the present invention forexample to protect against conditions such as hypothyroidism, in animalsincluding human beings.

The compositions of the present invention may be prepared by blending ofthe components or by wet or dry granulation. The blend or granulation isthen compressed into tablets.

A yet further aspect of the present invention provides a method for themanufacture of the solid oral dosage forms of the invention comprisingthe steps of:

(a) forming a first mixture by blending in intimate admixture one ormore disintegrant or disintegrants with a therapeutic agent comprisingone or more thyroid hormone or hormones;

(b) forming a second mixture by blending in intimate admixture one ormore disintegrant or disintegrants with a flavouring agent and alubricating agent;

(c) combining the first and second mixtures to form a pharmaceuticalcomposition; and

(d) compressing the composition from step (c) to form a fast dispersingsolid oral dosage form.

The invention will now be illustrated by the following non-limitingexamples in which % m/m indicates the amount of ingredient is given aspercentage by mass of the ingredient per total mass of the composition.The percentages may not total 100% due to rounding.

EXAMPLE 1

    ______________________________________                                        Fast dispersing formulation                                                   Ingredient            % m/m                                                   ______________________________________                                        Maize starch powder   33.15                                                   (disintegrant)                                                                Microcrystalline cellulose                                                                          15.00                                                   (Avicel PH101) (disintegrant)                                                 L-thyroxine           therapeutically                                                               effective  μg!                                                             amounts                                                 Maize starch powder   34.15                                                   (disintegrant)                                                                Microcrystalline cellulose                                                                          15.00                                                   (Avicel PH101) (disintegrant)                                                 B                                                                             Citric acid powder (saliva                                                                           2.00                                                   inducing agent)                                                               Aspartame (sweetener)  0.2                                                    Magnesium stearate powder                                                                            0.5                                                    (lubricant)                                                                   ______________________________________                                    

The ingredients marked A were mixed together and granulated. The powdersmarked B were mixed together and the resultant powder was mixed with thegranules from A to coat them. Optionally permitted colours may be addedat this stage. The coated granules were then compressed into tabletseach containing 50 μg levothyroxine sodium on an anhydrous basis, eachtablet having a hardness in the range from 1 to 3 kp. The resultingtablets were hard enough to survive in conventional packaging systemssuch as bottles or blister packs, were insoluble and dispersedcompletely as fine particles in the mouth within 10 to 15 seconds with apleasant taste and a good mouth feel.

EXAMPLE 2

    ______________________________________                                        Ingredient            % m/m                                                   ______________________________________                                        Microcrystalline cellulose                                                                          20.00                                                   (Avicel PH101)                                                                Levothyroxine sodium  Therapeutically                                                               effective amounts                                                             (μg)                                                 B                                                                             Maize starch powder   67.75                                                   Microcrystalline cellulose                                                                          10.00                                                   (Avicel PH101)                                                                Citric acid monohydrate                                                                              2.50                                                   powder                                                                        C                                                                             Permitted colour      qs                                                      powder                                                                        D                                                                             Magnesium stearate powder                                                                            0.50                                                   ______________________________________                                    

The ingredients marked A were triturated. The triturated material wasmixed the ingredients marked B. The mixture of A and B was granulatedwith purified water and dried to form granules, which were (optionally)mixed with the permitted colour (ingredient C). This mixture was finallyblended with the magnesium stearate (ingredient D). The final mixturewas compressed into tablets each containing 25 μg levothyroxine sodiumon an anhydrous basis, each tablet having a hardness in the range from 2to 6 kp. The resultant tablets were strong enough to survive inconventional packaging systems such as a bottle or blister packs. Thetablets were insoluble and dispersed completely as fine particles in themouth within 10 to 15 seconds with a pleasant taste and mouth feel.

We claim:
 1. A solid dispersing dosage form of a pharmaceuticalcomposition for oral administration which disintegrates in the mouth,the dosage form comprising: a therapeutic agent which comprises 0.1 μgto about 10,000 μg of one or more thyroid hormone or hormones; aneffective amount of from about 80% to about 99.9% of disintegratingagent by mass; from about 0.01% to about 10% of flavoring agent by mass;and from about 0.1% to about 5% of lubricating agent by mass.
 2. Adosage form as claimed in claim 1; in which the thyroid hormonecomprisesL-3,5,3',5'-tetraiodothyronine; L-3,5,3'-triiodothyronine;L-3,3',5'-triiodothyronine; L-3,5-diiodothyronine; pharmaceuticallyacceptable salts thereof; or any mixtures thereof.
 3. A dosage form asin claim 1, in which the disintegrating agent comprises a blend of atleast two components.
 4. A dosage form as in claim 3, in which eachcomponent independently comprises an ingredient selected frompharmaceutically acceptable starch, modified starch, methyl cellulose,agar, bentonite, cellulose, microcrystalline cellulose, alginic acid,guar gum, carboxymethylcellulose and sodium lauryl sulphate.
 5. A dosageform as in claim 1, in which composition comprises an ingredient oringredients which induces the formation of saliva.
 6. A method oftreating disorders associated with an impairment of the thyroid hormonefunction in animals including human beings, which comprises theadministration to a patient in need thereof a therapeutically effectiveamount of a solid oral dosage form which disintegrates in the mouth,said dosage form containing from about 0.1 μg to about 10,000 μg of oneor more thyroid hormone or hormones; an effective amount of from about80% to about 99.9% of disintegrating agent by mass based on the mass ofthe dose; from about 0.01% to about 10% of flavoring agent by mass basedon the mass of the dose; and from about 0.1% to about 5% of lubricatingagent by mass based on the mass of the dose.
 7. A method for themanufacture of a solid oral dosage form, comprising the steps of:(a)forming a first mixture by blending in intimate admixture one or moredisintegrant or disintegrants with a therapeutic agent comprising one ormore thyroid hormone or hormones; (b) forming a second mixture byblending in intimate admixture one or more disintegrant or disintegrantswith a flavouring agent and a lubricating agent; (c) combining the firstand second mixtures to form a pharmaceutical composition; and (d)compressing the composition from step (c) to form a fast dispersingsolid oral dosage form.
 8. A method of preparing a solid dispersingdosage form of a pharmaceutical composition for oral administration, themethod comprising: combining a therapeutic agent which comprises one ormore thyroid hormones, and an effective amount of from about 80% toabout 99.9% by mass of disintegrating agent based on the mass of thedose; and from about 0.01% to about 10% by mass of flavoring agent basedon the mass of the dose; followed by from about 0.1% to about 5% by massof lubricating agent based on the mass of the dose.
 9. A method as inclaim 8; in which the thyroid hormonecomprisesL-3,5,3',5'-tetraiodothyronine; L-3,5,3'-triiodothyronine;L-3,3',5'-triiodothyronine; L-3,5-diiodothyronine; pharmaceuticallyacceptable salts thereof; or any mixtures thereof.
 10. A method as inclaim 8, in which the disintegrating agent comprises a blend of at leasttwo components.
 11. A method as in claim 10, in which each componentindependently comprises an ingredient selected from pharmaceuticallyacceptable starch, modified starch, methyl cellulose, agar, bentonite,cellulose, microcrystalline cellulose, alginic acid, guar gum,carboxymethylcellulose and sodium lauryl sulphate.
 12. A method as inclaim 8, in which an ingredient or ingredients which induces theformation of saliva is added to the composition.